OVERALL DESCRIPTION (provided by applicant: The primary objective of research at the University of Virginia has been to understand the role of foreign antigens or allergens in causing and maintaining the chronic inflammation of asthma. However, it has become clear that many factors contribute to the severity of the disease, including: viral infections, chronic hyperplastic sinusitis, the nature of the immune response to allergens and the biochemistry of the lung response, including the recently recognized fall in pH. The current application will focus on four different aspects of this interaction. Project 1 will investigate the mechanisms that control the pH of lung lining fluid, including decreased glutaminase with the resulting fall in ammonia. The hypothesis is that glutaminase can be downregulated by interferon-gamma (IFN-gamma) from T cells responding to rhinovirus (RV), and that the pH fall acts on already inflamed lung to exacerbate attacks of asthma. Project 2 focuses on the relationship between chronic sinusitis and asthma using prospective studies, analysis of the response to allergen or viral challenge, and detailed investigation of the relevance of the leukotriene receptors, CysLTR1 and CysLTR2, to inflammation of the sinuses. Project 3 continues studies on the role of viral infections in asthma by studying infants and children hospitalized for asthma/bronchiolitis and by defining the role of pre-existing inflammation and IgE antibody (Ab) in the response to rhinoviral challenge. These studies will play an important role in interacting with each of the other projects. Project 4 will investigate the recent finding that exposure to high levels of the cat allergen, Fel d 1, can induce a "modified T helper (Th)2" response with IgG Ab and IgG4 Ab but without IgE Ab. These studies will examine the relevance of this response to symptoms, asthma and the response to other allergens in ongoing prospective studies in children. The mechanisms controlling the form of immunological tolerance will be investigated by studying the specificity and cytokine response of Fel d 1-specific T cells in vitro. Overall, the studies are designed to understand: 1) the immunological and biochemical events that underlie acute episodes of asthma; 2) the relationship between responses of the nose and sinuses to allergen or viral exposure and subsequent events in the lungs; and 3) the aspects of the immune response to allergens that explain why so many allergic patients are being treated for asthma and admitted to hospital with asthma. Understanding the mechanisms involved is essential for defining new approaches to treatment and prevention and also for explaining the increasing prevalence of asthma.